The skin has two compartments, one which is superficial, the epidermis, and one which is deeper, the dermis, which interact. The natural human epidermis is mainly composed of three types of cell which are the keratinocytes, which form the great majority, the melanocytes and the Langerhans' cells.
The epidermis is conventionally divided into a basal layer of keratinocytes constituting the germinative layer of the epidermis, a so-called prickle cell layer consisting of several layers of polyhedral cells arranged on the germinative layers, one to three so-called granular layers consisting of flattened cells containing distinct cytoplasmic inclusions, the keratohyalin granules and finally the horny layer (or stratum corneum), consisting of a set of layers of keratinocytes at the final stage of their differentiation, called corneocytes. The corneocytes are anucleated cells mainly composed of a fibrous matrix containing cytokeratins, surrounded by a very resistant structure 15 nm thick, called horny or hornified envelope. The stacking of these corneocytes constitutes the horny layer which is responsible for the barrier function of the epidermis. During the normal desquamation process, the most superficial corneocytes become detached from the surface of the epidermis.
Intercellular structures derived from desmosomes, called corneosomes or corneodesmosomes, have been described in the horny layer. They are of major importance in intercorneocyte cohesion and in the desquamation process. In particular, a close correlation exists between cell dissociation and proteolysis of certain corneodesmosomal components such as desmoglein I or corneodesmosin.
Several trypsin or chymotrypsin type serine proteases appear to be involved in the proteolysis of the corneodesmosomes, in particular the chymotryptic enzyme of the horny layer (stratum corneum chymotryptic enzyme).
The dermis provides the epidermis with a solid support. It is also its feeder component. It consists mainly of fibroblasts and an extracellular matrix predominantly composed of collagen, elastin and a substance called ground substance. Leukocytes, mastocytes or tissue macrophages are also present. Finally, the dermis is crossed by blood vessels and nerve fibres.
The cohesion between the epidermis and the dermis is provided by the dermoepidermal junction.
The epidermal homeostasis corresponds to an equilibrium between the keratinocytes entering into differentiation in the deep layers of the epidermis and corneocytes removed from the surface of the epidermis in a process called desquamation. Normally, desquamation occurs corneocyte by corneocyte and remains imperceptible.
Desquamation has in the past been associated with mechanical actions. This so-called bricks and mortar theory, the bricks being the corneocytes linked to each other by a lipid mortar (P. Elias, 1984), was contradicted only by the discovery of cohesive structures derived from the desmosomes called corneodesmosomes linked to the horny envelope and to the intermediate filaments of keratins (Chapman, Walsh et al. 1991; Serre, Mils et al. 1991; Walsh and Chapman 1991). The proteins which constitute these structures are the substrates for the desquamation enzymes. Indeed, the gradual appearance of fragments of desmosomal proteins during differentiation and the apparent ultrastructural modifications of the desmosome have led researchers in the direction of enzymes responsible for these changes.
The first, T. Egelrud (Egelrud, Hofer et al. 1988; Egelrud and Lundstrom 1990; Egelrud and Lundstrom 1991), has demonstrated in the stratum corneum (SC) the existence of protease activities of the “trypsin-like” and especially “chymotrypsin-like” type associated with desquamation. These studies by T. Egelrud are part of the basic studies of any research relating to the bio-chemistry of desquamation. Subsequently, several cysteine and aspartic acid proteases were implicated in this process, in particular the stratum corneum thiol protease (SCTP) or cathepsin L2, the stratum corneum cathepsin L-like (SCCL) and cathepsin D.
In a number of situations, it may be desirable to stimulate this desquamation mechanism in order to promote epidermal renewal and improve the brightness of the complexion, attenuate surface irregularities and smoothe the skin, or to promote the cleansing action and the removal of dead cells at the surface of the body. In physiological states, thickening of the horny layer is also observed which it is desired to limit, for example in the case of callosites or after exposure to sunlight. Moreover, in some skin disorders, desquamation becomes visible and it is large sized scales containing numerous corneocytes which are removed. Deregulations of desquamation are increasingly better described at the molecular level and associated with aspects of abnormal skin.
Ichthyoses are generally examples of impaired epidermal differentiation associated with abnormal desquamation. In psoriasis, an inflammatory skin disease, and atopic dermatitis, it has also been possible to show disorders associated with abnormal desquamation. In the field of acne, the accumulation of a keratin plug (which can be removed by protease activities) obstructing the pores is one of the reasons for the appearance of comedones. The appearance of dandruff is another example of a desquamation defect where the scales are abnormally visible. The impaired desquamation which is generally present in reconstructed epidermes (Vicanova, Mommaas et al. 1996) also represents a proteolytic defect. Some pathological skins can benefit from prodesquamating treatment based on urea derivatives. Among these pathologies, there may be mentioned the Netherton syndrome, the Papillon-Lefèvre syndrome, more generally ichthyoses of genetic origin and psoriasis or atopic dermatitis and the like.
Various methods have already been proposed for promoting desquamation, in particular by peeling or scrubbing. It is also possible to use in particular retinoic acid and its derivatives, x-hydroxy acids, such as lactic acid or glycolic acid, or β-hydroxy acids, such as salicylic acid.
However, the active agents proposed, although they give good results, often have a proteolytic and/or keratolytic activity which may lead to irritation of the areas where they are applied. Moreover, the addition of exogenous protease to compositions can pose problems of stabilization, irritation and create an allergy risk for subjects to whom they are applied.
The prodesquamating properties of urea are generally associated with its protein-denaturing properties (so-called “keratolytic” effect). Urea is thought to denature certain corneodesmosomal substrates promoting, inter alia, the action of certain proteases. On the other hand, this effect is not a lasting effect capable of stimulating the natural desquamation processes because urea in the end, especially at concentrations greater than 2M, becomes denaturing for the proteases themselves. It would therefore be advantageous to find a compound capable of durably stimulating the proteolytic activities of the stratum corneum.
Some cosmetic active agents are capable of stimulating the degradation of the proteins of the corneodesmosome and therefore desquamation. Patent application EP 852 949 (Shiseido) describes the use, as desquamating agent, of derivatives of alpha-amino acids of the glycine type, which favour the degradation of desmoglein (corneodesmosome protein).